Process for preparation of darunavir

ABSTRACT

Provided are a process for preparation of darunavir or solvates or a pharmaceutically acceptable salt thereof substantially free of bisfuranyl impurities and a process for preparation of amorphous darunavir using the darunavir propionate solvate.

PRIORITY

This application claims the benefit under Indian Provisional ApplicationNo. 3021/CHE/2012, filed Jul. 24, 2012, the content of each of which isincorporated by reference herein.

FIELD OF THE INVENTION

The present invention generally relates to a process for preparation ofDarunavir or solvates or a pharmaceutically acceptable salt thereofsubstantially free of bisfuranyl impurities and pharmaceuticalcompositions containing the same.

The present invention also relates to a process for preparation ofamorphous Darunavir or a solvates or a pharmaceutically acceptable saltthereof and pharmaceutical compositions containing the same.

BACKGROUND OF THE INVENTION

Darunavir, also known as[(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamicacid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester, is representedby the structural Formula I:

Darunavir is an inhibitor of the HIV protease belonging to the class ofhydroxyethyl amino sulfonamides and is available as its ethanolatesolvate under the name PREZISTA in the form of Eq75 mg, 150 mg, 400 mgand 600 mg base oral tablets and Eq100 mgbase/ml oral suspension.

Darunavir was first generically disclosed in U.S. Pat. No. 5,843,946(“the 946 patent”) and specifically disclosed in U.S. Pat. No. 6,248,775(“the 775 patent”). The '775 patent further discloses a process for thepreparation of darunavir active moiety,[(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamicacid of Formula II by reactingN-[3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl]-N-isobutylamine with4-nitrobenzene sulfonyl chloride in presence of triethyl amine followedby hydrogenating the resultant nitro compound with palladium carbon. The'775 patent does not disclose any enabling disclosure for thepreparation of darunavir (hexahydrofuranyl ester of Formula II). Theprocess disclosed in the '775 patent is schematically represented asfollows:

The '775 patent process involves simultaneous reduction of the nitromoiety and CBz deprotection in intermediate nitro compound results in ahighly exothermic reaction that generates unwanted side reactions withthe result that decreasing the product selectivity.

The first synthesis of darunavir was described in A. K. Ghosh et al.Bioorganic & Medicinal Chemistry Letters 8 (1998) 687-690, which isherein incorporated by reference. The synthesis includes reacting azidoepoxide with isobutylamine and treatment of the resultant azido alcoholwith p-nitrobenzene sulfonyl chloride to afford nitro compound. Thenitro compound was hydrogenated with Palladium catalyst and thenresultant amine compound was transformed to darunavir upon reaction withhexahydrofuro[2,3-b]furan-3-yl derivative in methylene chloride in thepresence of 3 equivalents of triethylamine at 23° C. for 12 hours.

The process disclosed in the A. K. Ghosh et al is not suitable forlarge-scale production because it involves hazardous azide compounds;thus it requires utmost care to use. The process disclosed in the A. K.Ghosh et al is schematically represented as follows:

To overcome the difficulties associated with the A. K. Ghosh et al,alternate processes were disclosed, for example U.S. Pat. No. 7,772,411(“the '411 patent”) discloses the preparation of darunavir usingboc-epoxide instead of azido epoxide as starting material. The '411patent process involves a) reaction of boc epoxide with isobutylamine,b) introducing the p-nitrobenzene sulfonyl chloride c) reducing thenitro moiety d) deprotecting the boc protection and e) coupling theamine compound with hexahydrofuro[2,3-b]furan-3-yl derivative in amixture of ethyl acetate and acetonitrile and in the presence oftriethyl amine and methyl amine in aqueous ethanol.

Although the '411 patent process involves boc-epoxide instead ofhazardous azido epoxide, the process still have difficulty to operate onlarge scale as it involves multistage synthesis hence the overall yieldis limited to about 50%. The process disclosed in the '411 patent isschematically represented as follows:

PCT Publication No. WO 2010/023322 (“the '322 publication”) discloses analternate process of darunavir by a) reaction of boc-epoxide withN-benzyl-isobutylamine, b) deprotecting the amine protecting group c)coupling the amine compound with hexahydrofuro[2,3-b]furan-3-ylderivative d) removing the N-benzyl group e) introducing thep-nitrobenzene sulfonyl chloride and f) reducing the nitro moiety. The'322 publication process also involves multistep synthesis, this leadsto an increase in the manufacturing cycle time. The process disclosed inthe '322 publication process is schematically represented as follows:

PCT Publication No. WO 2011/051978 (“the '978 publication”) discloses analternative process of darunavir by introducing furanyl compound beforethe nitro group reduction. This publication mention that the synthesisof darunavir by coupling of Formula II withhexahydrofuro[2,3-b]furan-3-yl derivative very likely leads to formationof impurities, viz., Impurity A and Impurity B.

The process disclosed in the '978 publication process is schematicallyrepresented as follows:

PCT Publication No. WO 2011/048604 (“the '604 publication”) discloses aprocess for preparation of darunavir having bisfuranyl Impurity ofFormula C less than 0.1% by coupling the4-Amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenyl)-N-(isobutyl)benzenesulfonamide with (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivativeusing N-methyl-2-pyrrolidinone as reaction solvent. The '604 publicationfurther disclosed amorphous darunavir having particle size D50 ofapproximately 50 micrometers and D90 of approximately 100 to 180micrometers.

PCT Publication No. WO 2011/092687 (“the '687 publication”) discloses aprocess for preparation of darunavir by following scheme:

PCT Publication No. WO 2013/011485 (“the 485 publication”) discloses aprocess preparation of darunavir by following scheme:

Darunavir can exist in different polymorphic forms, which differ fromeach other in terms of stability, physical properties, spectral data andmethods of preparation.

Several pseudopolymorphic forms of darunavir are described in theliterature, for example U.S. Patent Application No. 2005/0250845disclosed darunavir amorphous Form, Form A (ethanolate), Form B(hydrate), Form C (methanolate), Form D (acetonate), Form E(dichloromethanate), Form F (ethylacetate solvate), Form G(1-ethoxy-2-propanolate), Form H (anisolate), Form I(tetrahydrofuranate), Form J (isopropanolate) and Form K (mesylate) ofdarunavir.

Journal of Molecular Biology, Vol 338, No 2, 23 Apr. 2004, pages 341-352discloses the preparation of darunavir as white amorphous solid.

Amorphous Darunavir preparation was described in several ways in theliterature, for example in WO2011/048604, WO2011/073993, WO 2011/083287,WO 2011/145099 & IN 2548/CHE/2009. Further WO2010/086844 describes theamorphous form of Darunavir with IR spectrum with characteristic peaksabout 1454 and 1369 cm⁻¹.

The processes for preparation of darunavir described in the aboveliterature have certain drawbacks as it involves: a) harsh reactionconditions for example nitro reduction using palladium carbon andhydrogen gas may lead to decomposition of sensitive carbamate linkageand further requires special pressure equipments for carrying out thesynthesis, b) use of multiple solvents and bases during the introductionof furanyl ring makes the process not viable for large scalemanufacturing.

Further darunavir obtained from the above processes was not satisfactoryfrom purity point of view. Darunavir synthetic procedures as describedin the art contained relatively large amounts of impurities, forexample, when replicating the process of the '411 patent resulted in theelevation of bisfuranyl impurities. Extensive purification proceduresare required in order to limit the impurities to less than the requiredas per regulatory guidelines; results low product yield thereby makingthe process quite expensive.

Hence there remains a need for an improved process to prepare darunavir,particularly amorphous form of darunavir, which is cost effective,industrially viable, and provide darunavir substantially free ofimpurities.

OBJECT OF THE INVENTION

The main object of the invention is to provide a simple, cost effectiveprocess for the preparation of darunavir with high purity and yieldeither without the formation or minimizing the formation of undesiredimpurities.

Another object of the invention is to provide a process for thepreparation of darunavir wherein the process excludes the use ofmultiple solvents and multiple bases instead of use simple waterimmiscible organic solvent and water without use of any base during thereaction of amine compound of Formula II and(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivative, therebyminimizing the formation of bisfuranyl impurities, making the processmore suitable for commercial applications.

Yet another object of the invention is to provide a process for thepreparation of darunavir wherein the process excludes the use of nitrocompounds thereby avoiding harsh nitro reductions using palladium withhydrogen gas, making the process more convenient and safe to use on anindustrial scale.

SUMMARY OF THE INVENTION

The present invention encompasses a process for the preparation ofdarunavir or solvates or a pharmaceutically acceptable salt thereof withhigh product yield and quality, particularly darunavir in amorphous formsubstantially free of bisfuranyl impurities.

In accordance with one embodiment, the present invention provides aprocess for preparation of darunavir of Formula I or solvates or apharmaceutically acceptable salt thereof,

comprising:

-   -   a) reacting        4-amino-N-(2R,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamide        of Formula II

-   -    with (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivative in        a mixture of water immiscible organic solvent and water, and    -   b) isolating darunavir.

In accordance with a second embodiment, the present invention provides aprocess for preparation of darunavir, comprising:

-   -   a) reacting        4-amino-N-(2R,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamide        of Formula II with (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol        derivative in a mixture of water immiscible organic solvent and        water, and    -   b) isolating darunavir;        wherein the water immiscible organic solvent is selected from        the group consisting of esters, ethers, halogenated        hydrocarbons, aromatic hydrocarbons and the like.

In accordance with a third embodiment, the present invention provides aprocess for preparation of darunavir, comprising:

-   -   a) reacting        4-amino-N-(2R,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamide        of Formula II with (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol        derivative in a mixture of water immiscible organic solvent and        water, and    -   b) crystallizing darunavir from a carboxylic acid solvent, and    -   c) isolating the darunavir.

In accordance with a fourth embodiment, the present invention provides aprocess for preparation of darunavir, comprising:

-   -   a) reacting        4-amino-N-(2R,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamide        of Formula II with (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol        derivative in a mixture of water immiscible organic solvent and        water, and    -   b) crystallizing darunavir from a carboxylic acid solvent,    -   c) isolating the corresponding darunavir carboxylic acid        solvate, and    -   d) converting the darunavir carboxylic acid solvate in to        darunavir.

In accordance with a fifth embodiment, the present invention provides aprocess for preparation of darunavir, comprising:

-   -   a) reacting        4-amino-N-(2R,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamide        of Formula II with (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol        derivative in a mixture of water immiscible organic solvent and        water, and    -   b) crystallizing darunavir in propionic acid,    -   c) isolating the darunavir propionate solvate, and    -   d) converting the darunavir propionate solvate in to darunavir.

In accordance with a sixth embodiment, the present invention providesdarunavir propionate solvate.

In accordance with a seventh embodiment, the present invention providesdarunavir propionate characterized by an X-Ray diffraction (XRD) patternsubstantially in accordance with FIG. 1.

In accordance with an eighth embodiment, the present invention providesa process for preparation of4-amino-N-(2R,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamideof Formula II,

comprising:

-   -   a) reacting a compound of Formula IV

wherein ‘P₁’ represents hydrogen or a suitable amine protecting groupselected from the group consisting of acetyl, tertiary butyloxy carbonyl(Boc), p-nitrobenzoyl (PNB), p-methoxybenzoyl (PMB), trityl and thelike, with a protected benzene sulfonyl chloride of Formula IV′

wherein ‘P₂’ represents hydrogen or a suitable amine protecting groupselected from the group consisting of acetyl, tertiary butyloxy carbonyl(Boc), p-nitrobenzoyl (PNB), p-methoxybenzoyl (PMB), trityl and thelike; to obtain a compound of Formula III

wherein ‘P₁’ and ‘P₂’ represents hydrogen or a suitable amine protectinggroup, and

-   -   b) deprotecting the resultant compound with a suitable        deprotecting medium.

In accordance with a ninth embodiment, the present invention provides aprocess for preparation of darunavir of Formula I or solvates or apharmaceutically acceptable salt thereof,

comprising:

-   -   a) reacting a compound of Formula IV

wherein ‘P₁’ represents hydrogen or a suitable amine protecting groupselected from the group consisting of acetyl, tertiary butyloxy carbonyl(Boc), p-nitrobenzoyl (PNB), p-methoxybenzoyl (PMB), trityl and thelike, with a protected benzene sulfonyl chloride of Formula IV′

wherein ‘P₂’ represents hydrogen or a suitable amine protecting groupselected from the group consisting of acetyl, tertiary butyloxy carbonyl(Boc), p-nitrobenzoyl (PNB), p-methoxybenzoyl (PMB), trityl and thelike; to obtain a compound of Formula III

wherein ‘P₁’ and ‘P₂’ represents hydrogen or a suitable amine protectinggroup selected from the group consisting of acetyl, tertiary butyloxycarbonyl (Boc), p-nitrobenzoyl (PNB), p-methoxybenzoyl (PMB), trityl andthe like,

-   -   b) deprotecting the resultant compound with a suitable        deprotecting medium to obtain a compound of Formula II,

-   -   c) reacting the resultant compound of Formula II with        (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivative in a        mixture of water immiscible organic solvent and water,    -   d) crystallizing darunavir in carboxylic acid,    -   e) isolating the darunavir carboxylic acid solvate, and    -   f) converting the darunavir carboxylic acid solvate in to        darunavir.

In accordance with a tenth embodiment, the present invention provides aprocess for preparation of darunavir of Formula I or solvates or apharmaceutically acceptable salt thereof,

comprising:

-   -   a) reacting (1-benzyl-2-hydroxy-3-isobutylaminopropyl)carbamic        acid tertiary butyl ester of Formula

with a N-acetyl benzene sulfonyl chloride of Formula

to obtain a compound of Formula III

-   -   b) deprotecting the resultant compound with an acid to obtain        4-amino-N-(2R,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamide        of Formula II,

-   -   c) reacting the resultant compound of Formula II with        (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivative in a        mixture of water immiscible organic solvent and water,    -   d) crystallizing darunavir in carboxylic acid,    -   e) isolating the darunavir carboxylic acid solvate, and    -   f) converting the darunavir carboxylic acid solvate in to        darunavir.

In accordance with an eleventh embodiment, the present inventionprovides a process for preparation of amorphous darunavir, comprisingthe steps of:

-   -   a) providing a solution of darunavir in any form or obtained by        the processes herein described above in an acid and water,    -   b) combining step a) solution and a solution of a base and        water,    -   c) recovering amorphous darunavir.

In accordance with a twelfth embodiment, the present invention providesa process for preparation of amorphous darunavir, comprising the stepsof:

-   -   a) providing a solution of darunavir or solvates or a        pharmaceutically acceptable salt thereof, obtained by the        processes herein described above in an acid and a solvent        optionally a base,    -   b) combining step a) solution and a solution of a base and        water,    -   c) recovering amorphous darunavir.

In accordance with a thirteenth embodiment, the present inventionprovides a process for preparation of amorphous darunavir, comprisingthe steps of:

-   -   a) providing a solution of darunavir or solvates or a        pharmaceutically acceptable salt thereof, obtained by the        processes herein described above in an acid and a solvent        optionally a base,    -   b) combining step a) solution and a solution of a base and        water,    -   c) recovering amorphous darunavir;    -   wherein the acid is an organic acid, the solvent is selected        from the group comprising nitriles, alcohols, water and the like        and the base in an inorganic base.

In accordance with a fourteenth embodiment, the present inventionprovides a process for preparation of amorphous darunavir, comprisingthe steps of:

-   -   a) providing a solution of darunavir propionate solvate in        acetic acid, acetonitrile and ammonia,    -   b) combining step a) solution and a solution of a ammonia and        water,    -   c) recovering amorphous darunavir.

In accordance with a fifteenth embodiment, the present inventionprovides pharmaceutical composition comprising darunavir or solvates ora pharmaceutically acceptable salt thereof prepared by the processes ofthe present invention and at least one pharmaceutically acceptableexcipient.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate several embodiments of theinvention and together with the description, serve to explain theprinciples of the invention.

FIG. 1 is the characteristic powder X-ray diffraction (XRD) pattern ofdarunavir propionate.

FIG. 2 is the characteristic powder X-ray diffraction (XRD) pattern ofamorphous darunavir.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses a process for the preparation ofdarunavir or solvates or a pharmaceutically acceptable salt thereof withhigh product yield and quality and substantially free of bisfuranylimpurities. In particular, the present invention provides a process toprepare darunavir, wherein the process excludes the use of multiplesolvents and harsh nitro reduction step thereby process more convenient,economical and safe to use on an industrial scale.

In one embodiment, the present invention provides a process forpreparation of darunavir of Formula I or a solvate or a pharmaceuticallyacceptable salt thereof;

comprising:

-   -   a) reacting a compound of Formula IV

wherein ‘P₁’ represents hydrogen or a suitable amine protecting group,with a protected benzene sulfonyl chloride of Formula IV′

wherein ‘P₂’ represents hydrogen or a suitable amine protecting group;to obtain a compound of Formula III

wherein ‘P₁’ and ‘P₂’ represents hydrogen or a suitable amine protectinggroup,

-   -   b) deprotecting the resultant compound with a suitable        deprotecting medium to obtain        4-amino-N-(2R,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamide        of Formula II

-   -   c) reacting the resultant compound of Formula II with        (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivative in a        mixture of water immiscible organic solvent and water, and    -   d) isolating darunavir.

As used herein, the term “suitable amino protecting group” refers to amoiety that can be selectively attached to and removed from a nitrogenatom to prevent it from participating in undesired chemical reactions,without unacceptably adverse affects on desired reactions. Examples ofamino protecting groups include, but are not limited to acetyl, tertiarybutyloxy carbonyl (Boc), p-nitrobenzoyl (PNB), p-methoxybenzoyl (PMB),trityl and the like.

In a preferred embodiment, the suitable amine protecting group ‘P₁’represents tertiary butyloxy carbonyl (Boc) and ‘P₂’ represents acetylgroup.

The starting material, a compound of Formula IV, when P₁ representstertiary butyloxy carbonyl, is known in the art and can be prepared byany known method, for example starting Formula IV may be synthesized asdisclosed in U.S. Pat. No. 7,772,411.

The reaction of compound of Formula IV, wherein P₁ represents tertiarybutyloxy carbonyl with protected benzene sulfonyl chloride of FormulaIV′, wherein P₂ represents acetyl group, carried out in an organicsolvent in presence of a base to obtain a compound of Formula III.

The organic solvent includes, but is not limited to halogenatedhydrocarbons, aromatic hydrocarbons, ethers, amides, nitriles and thelike and mixtures thereof. The halogenated hydrocarbons include, but arenot limited to methylene chloride, ethylene chloride, chloroform, carbontertrachloride and the like and mixtures thereof; aromatic hydrocarbonsinclude, but are not limited to toluene, xylene, chlorobenzene and thelike and mixtures thereof; ethers include, but are not limited todimethyl ether, diethyl ether, methyl ethyl ether, diisopropyl ether,methyl tertiary butyl ether, tetrahydrofuran, 1,4-dioxane and the likeand mixtures thereof; amides include, but are not limited to dimethylformamide, dimethyl acetamide, N-methyl pyrrolidinone, hexamethylphosphoramide and the like and mixtures thereof; nitriles include, butare not limited to acetonitrile, propionitrile and the like and mixturesthereof; preferably methylene chloride, toluene; more preferablymethylene chloride.

The base includes, but are not limited to sodium hydroxide, potassiumhydroxide, lithium hydroxide, sodium carbonate, potassium carbonate,lithium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia,methyl amine, ethyl amine, dimethylamine, diethylamine, triethylamineN,N-diisopropyl ethyl amine, N,N-dimethylaniline, N,N-dimethylaminopyridine and the like and mixtures thereof; preferably sodiumbicarbonate.

According to step b) of the foregoing process, the deprotection of thecompound of Formula III is carried out with a suitable deprotectingmedium. The suitable deprotecting medium may be includes by treatmentwith an acid in an organic solvent to obtain compound of Formula II.

The acid includes, but are not limited to hydrochloric acid, hydrobromicacid, sulfuric acid, perchloric acid, phosphoric acid, acetic acid,trifluoro acetic acid, trichloro acetic acid, methane sulfonic acid andthe like and mixtures thereof; preferably hydrochloric acid or sulfuricacid.

The organic solvent for step b) includes, but are not limited to loweralcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol,isobutanol and the like; nitriles such as acetonitrile, propionitrileand the like; ethers such as tetrahydrofuran, 1,4-dioxane and the like;amides such as dimethyl formamide, dimethyl acetamide and the like;water and mixtures thereof; preferably methanol, acetonitrile, dimethylformamide; more preferably methanol.

The reaction temperature should be sufficient to effect deprotectionreaction. Typically the reaction temperature may be from about ambienttemperature to about reflux temperature. The reaction may take fromabout 2 hours to about 12 hours depending upon the acid, solvent andtemperature chosen, preferably about 2 to 4 hours. Preferably thereaction completion at a temperature of about 40° C. to 45° C. for aperiod of about 8 hours.

In another embodiment, the present invention provides a process forpreparation of darunavir or a solvate or a pharmaceutically acceptablesalt thereof, comprising reacting4-amino-N-(2R,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamideof Formula II with (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-olderivative in a mixture of water immiscible organic solvent and water.

The compound of Formula II may be taken either as a starting material oras an intermediate prepared by the process described above.

Reported literature for coupling reaction of compound of Formula II with(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivative involves multiplesolvents and bases, for example process disclosed in the '411 patentinvolves use of ethyl acetate, acetonitrile and in presence of triethylamine and methyl amine in ethanol for the coupling reaction, which isdisadvantageous for both economic and environmental reasons.

In contrast to the use of multiple solvents and bases the presentinventors have now found a procedure in which the reaction is conductedin a mixture of water immiscible organic solvent and water without usingany base which provides significant advantages over the former methods.The inventors of the present invention have surprisingly found that theuse of certain solvent system enables the formation of darunavir withsubstantially lower levels of bisfuranyl impurities.

The (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol is advantageously anactivated derivative of hexahydrofuro[2,3-b]furan-3-ol of Formula V:

The compound of formula (V) above can be prepared in conventional mannerfor example as described in WO 03/022853, US 2004/0162340, WO2004/033462, U.S. Pat. No. 6,867,321, WO-2005/095410 and also Ghosh etal, J. Org. Chem. 2004, 69, 7822-7829.

The compound of formula (V) is suitably activated with a coupling agentto generate a hexahydrofuro[2,3-b]furan-3-yl derivative which is thenreacted with the compound of formula (II) to obtain the darunavir.

Examples of coupling agents used in reactions are carbonates such asbis-(4-nitrophenyl)carbonate, disuccinimidyl carbonate (DSC), carbonyldiimidazole (CDI). Other coupling agents include chloroformates, such asp-nitrophenylchloroformate, phosgenes such as phosgene, diphosgene andtriphosgene.

In particular, when (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol isreacted with disuccinimidyl carbonate,1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]-carbonyl]oxy)-2,5-pyrrolidinedioneof Formula V′ is obtained and is preferred(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivative.

The water immiscible organic solvent includes, but is not limited toesters, ethers, halogenated hydrocarbons, aromatic hydrocarbons and thelike. The esters include, but are not limited to methyl acetate, ethylacetate, isopropyl acetate and the like; ethers include, but are notlimited to diethyl ether, methyl tertiary butyl ether and the like;halogenated hydrocarbons include, but are not limited to methylenechloride, ethylene chloride, chloroform, carbon tertrachloride and thelike; aromatic hydrocarbons include, but are not limited to toluene,xylene, chlorobenzene and the like; and mixtures thereof; preferablyethyl acetate, methyl tertiary butyl ether, methylene chloride, tolueneand the like; more preferably ethyl acetate.

The reaction of compound of Formula II with(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivative is carried out ata suitable temperature. Typically the reaction temperature may be fromabout −10° C. to about 60° C. for a period of about 30 minutes to about8 hours. Preferably the reaction temperature is about room 20° C. toabout 30° C. for a period of about 2 hours to 5 hours.

After completion of the reaction, the reaction mass can be treated withan aqueous base solution, wherein the base is selected from any baseknown in the art, for example sodium hydroxide, potassium hydroxide,sodium carbonate, potassium carbonate and the like; and isolating thedarunavir by any method known in the art, for example by solventevaporation to obtain crude darunavir.

In another embodiment, the present invention provides a process forpreparation of darunavir in crystalline form, comprising a) treating anyform of darunavir or crude darunavir obtained just above with acarboxylic acid solvent and b) isolating the darunavir in crystallineform.

The carboxylic acid solvent used in step a) includes, but is not limitedto propionic acid.

Step a) of treating the darunavir with a carboxylic acid solvent furthercomprising the steps of: dissolving darunavir in a carboxylic acidsolvent. The solvent may be heated to obtain a solution at a temperatureof from about ambient temperature to about reflux temperature. Thereaction solution may be cooled at a temperature from about 30° C. orless such that the darunavir can be isolated by conventional techniques,for example filtration.

Darunavir recovered using the process of crystallization from acarboxylic acid solvent; preferably propionic acid of the invention issolvate form of darunavir, preferably darunavir propionate solvate.

In another embodiment, the present invention provides darunavirpropionate solvate.

In a further embodiment, the present invention provides characterizationvia X-ray powder diffraction pattern of a darunavir propionate solvate,which is substantially in accordance with FIG. 1. The X-Ray powderdiffraction can be measured by an X-ray powder Diffractometer equippedwith a Cu-anode ([λ]=1.54 Angstrom), X-ray source operated at 30 kV, 15mA and a Ni filter is used to strip K-beta radiation. Two-thetacalibration is performed using an NIST SRM 640c Si standard. The samplewas analyzed using the following instrument parameters: measuringrange=3-45° 20; step width=0.020°; and scan speed=2°/minute.

In another embodiment, the darunavir propionate solvate of the inventioncan be used as intermediate or as starting material for the preparationof darunavir in amorphous form.

In a further embodiment, the present invention provides a process forpreparation of amorphous darunavir, comprising:

-   -   a) providing a solution of darunavir in any form or obtained by        the processes herein described above in an acid and water,    -   b) combining step a) solution and a solution of a base and        water,    -   c) recovering amorphous darunavir.

In a further embodiment, the present invention provides a process forpreparation of amorphous darunavir, comprising:

-   -   a) providing a solution of darunavir or a solvate thereof,        obtained by the processes herein described above in an acid and        a solvent optionally a base,    -   b) combining step a) solution and a solution of a base and        water,    -   c) recovering amorphous darunavir.

Any form of darunavir can be used as starting material in the process ofmaking the amorphous darunavir of the present invention.

Ideally, darunavir propionate solvate, obtained by the processes hereindescribed previously, is the starting material in the process of makingthe amorphous darunavir.

Useful acids for carrying out the process for the preparation ofamorphous darunavir of the invention include carboxylic acid. Thecarboxylic acid include, but are not limited to acetic acid, propionicacid, formic acid, trifluoroacetic acid, butanoic acid, pentanoic acid,hexanoic acid, heptanoic acid and the like and mixtures thereof;preferably acetic acid.

The optional base used in step a) is selected from any base known in theart, for example the base include, but are not limited to ammonia,sodium carbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, cesium carbonate and the like and mixtures thereof;preferably ammonia.

The solvent used herein for step a) includes, but are not limited tonitriles such as acetonitrile, propionitrile and the like; alcohols suchas methanol, ethanol, isopropanol and the like; water and mixturesthereof; preferably acetonitrile or a mixture of acetonitrile and water.

The base used for step b) is any base known in the art, for example thebase used for optional step a) is used for step b).

The temperature for the preparation of solution in a) of the process canrange from about −20° C. to about 85° C.; preferably about 20° C. toabout 40° C.

Preferably, the step a) of the process for preparation of amorphousdarunavir consists of mixing darunavir propionate solvate in a mixtureof acetonitrile and acetic acid and then with ammonia to obtain a clearsolution, which is proceed for step b).

Combining step a) solution and a solution of a base and water can becarried out in any known manner, for example step a) solution is addedto a solution of base and water or the solution of base and water isadded to a solution of step a).

The temperature suitable for combining step a) solution and a solutionof base and water of step b) may be at about −20° C. to about 40° C.;preferably −10° C. to about 0° C.

The amorphous darunavir can be recovered by any conventional techniquesknown in the art, for example filtration. Typically, if stirring isinvolved, the temperature during stirring can range from about −10° C.to about 30° C. The resultant product may optionally be further dried bytechniques known in the art, for example tray drying under vacuum.

The present invention advantageously provides darunavir or a solvate ora pharmaceutically acceptable salt thereof, obtained by the processdescribed herein, having a chemical purity of at least about 98%, asmeasured by HPLC, preferably at least about 99%, as measured by HPLC,and more preferably at least about 99.8%, as measured by HPLC;substantially free of one or more impurities as described in Table 1:

Impurity A

Impurity B

Impurity C

Impurity D

Formula II

Isocyanate Impurity

N-Acetyl Darunavir

(R,S)-diastereomer

(S,S)-diastereomer

(R,R)-diastereomer

wherein the word “substantially free” refers to darunavir or a solvateor a pharmaceutically acceptable salt thereof having less than about0.1%, preferably less than 0.05% of Impurity A or Impurity B or ImpurityC or Impurity D or Formula II or Isocyanate Impurity or N-AcetylDarunavir or (R,S)-diastereomer or (S,S)-diastereomer or(R,R)-diastereomer, as measured by HPLC.

The reported literature for instance the '411 patent, '322 publicationand the '604 publication discloses process for the preparation ofdarunavir, which was involved either use of multiple solvents and baseduring the reaction of amine compound of Formula II and(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivative or involvingharsh nitro reduction steps, results darunavir contain high levels ofbisfuranyl impurities i.e. Impurity A, Impurity B or Impurity C orprocess related impurities i.e. Isocyanate Impurity or N-acetyldarunavir. In contrast, the process herein described arrives at adarunavir, which may be involved an improved process conditions such asmixture of simple water immiscible organic solvent and water instead ofmultiple solvents and base and avoids nitro reduction step.Particularly, the process herein described allows that a darunavir maybe prepared substantially lower level of above mentioned impurities.

The present invention provides darunavir or solvates or apharmaceutically acceptable salt thereof, obtained by the above process,as analyzed using the high performance liquid chromatography (“HPLC”)with the conditions described below:

-   -   Column: Symmetry shield, RP-18, 5 μm    -   Column temperature: 30° C.    -   Diluent: Water:Acetonitrile (1:1)    -   Flow rate: 1.0 mL/min    -   Detection wavelength: 215 nm    -   Injection volume: 10 μL

Mobile phase:

A) Buffer:Acetonitrile (9:1)

B) Buffer:Acetonitrile (3:7)

Buffer:Potassium dihydrogen phosphate in water at pH to 3.0 witho-phosphoric acid.

Gradient program:

Time (Min) Mobile phase A % (v/v) Mobile phase B % (v/v) 0 70 30 5 70 3030 25 75 40 10 90 60 10 90 65 70 30 75 70 30

The present invention provides darunavir in amorphous form, obtained bythe process disclosed herein, is characterized by an average size ofabout 40 μm for 50% of the particles, about 20 μm for 10% of theparticles and about 100 μm for 90% of the particles. The presentinvention further provides amorphous darunavir, obtained by the processdisclosed herein, is characterized by an average size of less than about40 μm for 50% of the particles, less than about 15 μm for 10% of theparticles and less than about 90 μm for 90% of the particles, obtainedupon milling.

Micronization is carried out by methods known in art such as jetmilling, media milling, pulverization and the like. The particle size ofthe amorphous darunavir obtained by the process of the invention can bedetermined by any method known in the art such as laser diffraction,sieve analysis, microscope observation, sedimentation and the like. Theparticle size measurement employed Malvern Mastersizer-2000, equippedwith Malvern hydro2000S (A) sample handling unit.

The present invention provides darunavir in amorphous form, obtained bythe process disclosed herein, is characterized by having bulk density ofparticles of about 0.5 g/ml. The present invention further providesamorphous darunavir, obtained by the process disclosed herein, ischaracterized by having bulk density of particles of about 0.4 g/ml.

The bulk density used tapped density tester dual-platform ETD-1020(Electrolab). System specifications: Speed: nominal rate of 300 taps perminute, Accuracy: Actual setting±1 tap, Drop height: 14±2 mm. Platformrotation: 5-15 rotations/minute.

Another embodiment of the present invention is directed to apharmaceutical composition containing at least the substantially puredarunavir or a solvate or a pharmaceutically acceptable salt thereof,particularly amorphous darunavir disclosed herein and at least onepharmaceutically acceptable excipient. Such pharmaceutical compositionmay be administered to a mammalian patient in any dosage form, e.g.,liquid, powder, elixir, injectable solution, etc.

The present invention has the following advantages with respect to thereported literature, are:

-   -   a) It involves simple water immiscible organic solvent and water        during the reaction of amine compound of Formula II and        (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivative, which        avoids formation of bisfuranyl impurities,    -   b) The process of the present invention herein described is        convenient and scalable as it carried out at room temperature        during the furanyl ester formation and addition of        (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivative in a        instantaneous instead of addition in prolonged period of time,    -   c) It avoids harsh nitro reductions using palladium with        hydrogen gas, making the process of more convenient and safe to        use on an industrial scale as it avoids decomposition of        carbamate linkage,    -   d) Darunavir prepared by the process of the present invention        has improved purity and contain substantially free of unwanted        bisfuranyl impurities.

EXAMPLES

The following non limiting examples illustrate specific embodiments ofthe present invention. They are not intended to be limiting the scope ofthe present invention in any way.

Example 1 Preparation of4-amino-N-(2R,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamideof Formula II

A 3 L round bottom flask fitted with a mechanical stirrer, thermometersocket, addition funnel was charged(1-benzyl-2-hydroxy-3-isobutylaminopropyl) carbamic acid tertiary butylester of Formula IV (100 gms) and MDC (1500 ml). The reactiontemperature was stirred for 10 minutes at 20° C. to 30° C. and to theresultant solution sodium bicarbonate (37.5 gms) and water (300 ml) wasadded. N-(Acetylamino)benzenesulfonyl chloride was charged in equal lots(4×19.1 gms) at about 25-30° C. The reaction was stirred at about25°-35° C. for about 2 hours and the reaction completion was monitoredby HPLC. After completion of the reaction, the layers were separated andorganic layer was washed with ammonia solution (200 ml) and then with aqHCl solution (9 ml of con. HCl+300 ml water). The layers were separatedand the MDC was distilled off completely to obtain residue. To theresidue, methanol (300 ml) and dil. sulfuric acid (145.6 gms of sulfuricacid+27 ml water) was added and the reaction temperature was raised to40° C. to 45° C. and maintained for about 8 hours and the reactioncompletion was monitored by HPLC. After completion of the deprotection,water (1000 ml) and toluene (50 ml) was charged and layers wereseparated. To the product containing aqueous layer, MDC (1200 ml) wascharged and allowed to cool to 0-5° C. and adjusted pH to about 12 withaqueous sodium hydroxide. The reaction mass temperature was raised toabout 25-30° C., stirred for 10 minutes and the organic layer wasseparated. The aqueous layer was extracted with MDC (300 ml) andseparated. The total organic layer was washed with water (2×300 ml) andthe MDC was distilled completely under vacuum at below 40° C. and theobtained residue was dissolved in ethyl acetate (500 ml) and methanol(40 ml) and stirred for 30 mins at 35-40° C. The reaction solution wasallowed to cool to 0° C. to 5° C. and stirred for about 60 minutes atsame temperature. Precipitated solid was filtered and washed withchilled ethyl acetate (50 ml). The wet product was dried at about 50° C.to about 55° C. under reduced pressure to provide the title compound.

Yield: 101 gms.

HPLC purity: 99.2%

Example 2 Preparation of4-amino-N-(2R,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamideof Formula II

A 3 L round bottom flask fitted with a mechanical stirrer, thermometersocket, addition funnel was charged(1-benzyl-2-hydroxy-3-isobutylaminopropyl) carbamic acid tertiary butylester of Formula IV (100 gms) and MDC (2000 ml). The reactiontemperature was stirred for 10 minutes at 20° C. to 30° C. andN-(Acetylamino)benzene sulfonyl chloride (79.8 gms) was charged. Thereaction mixture was allowed to cool to 10° C. and aqueous sodiumbicarbonate solution (1000 ml) was added. The reaction temperature wasraised to 25° C. to 30° C. and maintained for about 1 hour. The layerswere separated and organic layer was washed with ammonia solution (100ml) and then with DM water (500 ml). The layers were separated and theMDC was distilled off completely to obtain residue. To the residue,methanol (800 ml) and CP. HCl (125 ml) was charged and the reactiontemperature was raised to 60° C. to 65° C. and maintained for 4 hours.Methanol was distilled completely under vacuum at below 60° C. and theobtained residue was charged water (2200 ml) and ethyl acetate (2200ml). The reaction mass pH was adjusted to about 9 with aqueous sodiumhydroxide solution and layers were separated. The organic layer waswashed with water and the ethyl acetate was distilled under vacuum below40° C. up to minimum volume remains in the flask. The reaction solutionwas allowed to cool to 20° C. to 30° C. and stirred for about 60 minutesand further allowed to cool to 0° C. to 5° C. Precipitated solid wasfiltered and washed with ethyl acetate (100 ml). The wet product wasdried at about 50° C. to about 55° C. under reduced pressure to providethe title compound.

Yield: 102 gms.

HPLC purity: 99%

Example 3 Preparation of darunavir propionate solvate

A 2 L round bottom flask fitted with a mechanical stirrer, thermometersocket, addition funnel was charged1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]-carbonyl]oxy)-2,5-pyrrolidinedioneof Formula V (65.6 gms), ethyl acetate (1000 ml) and water (200 ml) at25° C. to 30° C. To the reaction mass Formula II (100 gms; obtained fromExample 1) was added at 25° C. to 30° C. and stirred for about 90-120minutes at same temperature and the reaction completion was monitored byHPLC. After completion of the reaction, the organic layer and theaqueous layers were separated and the organic layer was washed with 5%aqueous sodium bisulfate solution (2×300 ml; 15 gms of sodiumbisulfate+285 ml water) followed by with 10% aqueous potassium carbonatesolution (300 ml) and then with water (300 ml) and aqueous sodiumchloride solution (300 ml). Aqueous and organic layers were separatedand the organic layer was distilled off completely under vacuum at below40° C. to obtain residue. To the residue, ethyl acetate (25 ml) andpropionic acid (1000 ml) was added at temperature 15-20° C. and stirredfor about 30 mins at same temperature. The reaction mass was allowed tocool to 0-5° C. and stirred for about 90 mins. Precipitated solid wasfiltered and washed with chilled propionic acid (50 ml). The wet productwas dried at about 45° C. to about 50° C. under reduced pressure toprovide the title compound.

Yield: 135 gms.

HPLC purity: 99.3%

Formula II: 0.05%

The XRPD is set forth in FIG. 01

Example 4 Preparation of darunavir propionate solvate

A 2 L round bottom flask fitted with a mechanical stirrer, thermometersocket, addition funnel was charged1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]-carbonyl]oxy)-2,5-pyrrolidinedioneof Formula V (68 gms), ethyl acetate (1500 ml) and water (200 ml) at 25°C. to 30° C. To the reaction mass added Formula II (100 gms) at 25° C.to 30° C. and stirred for 60 minutes at same temperature. To thereaction mass charged 10% aqueous potassium carbonate (500 ml) andlayers were separated and the organic layer was washed with DM water(500 ml). The layers were separated and the ethyl acetate was distilledoff completely under vacuum to obtain residue (Darunavir: 97.1%, FormulaII: 2%, Impurity A: less than 0.10%, Impurity C: less than 0.05%). Tothe residue, charged propionic acid (1000 ml) and stirred for 60 minutesat 25° C. to 30° C. Precipitated solid was filtered and washed withpropionic acid (100 ml) followed by diisopropyl ether (200 ml). The wetproduct was dried at about 60° C. to about 70° C. under reduced pressureto provide the title compound.

Yield: 125 gms.

HPLC purity: 99.5%,

Formula II: 0.06%

The XRPD is set forth in FIG. 01

Experimental Data:

The impurity profile as measured by high performance liquidchromatography for three batches of darunavir propionate solvate of thepresent invention is set forth below in Table II.

TABLE II Batch Impurity A Impurity B Impurity C Impurity D 1 0.02% ND0.01% ND 2 0.05% ND 0.03% ND 3 0.04% ND 0.02% ND ND: Not detected

Example 5 Preparation of darunavir as procedure analogous to thatemployed in Example 3, using mixture of different water immisciblesolvent and water as described in the following Table III

TABLE III S. Formula II Water immiscible No (Example 1) Formula VSolvent Purity 01 0.5 gms 0.36 gms MDC + water Darunavir: 95.3%; FormulaII: 1.66% 02 0.5 gms 0.36 gms Toluene + water Darunavir: 99.58% FormulaII: 1.82%

Example 6 Preparation of amorphous darunavir

A 3 L round bottom flask fitted with a mechanical stirrer, thermometersocket, addition funnel was charged acetic acid (300 ml) andAcetonitrile (75 ml) at 25° C. to 30° C. The mass was allowed to cool to5-10° C. and darunavir propionate solvate (100 gms; obtained fromExample 3) was charged at same temperature. To the reaction mass, con.Ammonia solution (25 ml) was added at same temperature and the solutionwas allowed to cool to 0° C. to 5° C. and kept aside.

In another round bottom flask charged water (2000 ml) and ammonia (800ml) and allowed to cool to −10° C. to −5° C. To this solution, darunavirpropionate solution was added at a temperature of −10° C. to −5° C. andstirred for 30 minutes at same temperature. The reaction masstemperature was raised to about 15° C. and stirred for about 60 mins atsame temperature. Precipitated solid was filtered and washed with water(1000 ml). The wet product was slurred in water (2500 ml), filtered andwashed with water (1000 ml). The wet product was dried at about 45° C.to about 50° C. under reduced pressure to provide the title compound.

Yield: 77 Gms. HPLC purity: 99.7%

Impurity A 0.03% Isocyanate Impurity 0.01% Impurity B Not DetectedN-Acetyl Darunavir 0.03% Impurity C 0.04% (R,S)-diastereomer 0.03%Impurity D Not Detected (S,S)-diastereomer BDL Diamine 0.01%(R,R)-diastereomer BDL

LOD: 0.006%

The XRPD is set forth in FIG. 02

Example 7 Preparation of amorphous darunavir

A 3 L round bottom flask fitted with a mechanical stirrer, thermometersocket, addition funnel was charged water (800 ml) acetic acid (1000 ml)at 25° C. to 30° C. To the solution charged darunavir propionate solvate(100 gms; obtained from Example 2) at 15° C. to 20° C. and stirred for10 minutes at same temperature. The solution was allowed to cool to 0°C. to 5° C. and kept aside. In another round bottom flask charged water(2000 ml) and ammonia (850 ml) and allowed to cool to 0° C. to 5° C. Tothe solution of water and ammonia, added darunavir solution attemperature of −5° C. to 0° C. and stirred for 30 minutes at a sametemperature. Precipitated solid was filtered and washed with water (1000ml). The wet product was slurred in water (2000 ml), filtered and washedwith water (100 ml). The wet product was dried at about 25° C. to about35° C. under reduced pressure to provide the title compound.

Yield: 75 Gms.

HPLC purity: 99.7%, Impurity A: 0.02%, Impurity C: 0.03%, Impurity B &Impurity D: Not Detected

The XRPD is set forth in FIG. 02

Example 8 Characterization of Isocyanate Impurity and N-Acetyl Darunavir

¹HNMR (300 MHz, DMSO-d₆) : δ7.63 (s, 1H), 7.31(m, 2H), 7.24(m, 2H), 7.21(m, 2H), 7.18 (d, 2H, J=8.4Hz), 6.55(d, 2H, J=8.1 Hz), 5.98(s, 2H),4.69(m, 1H), 4.22(q, 1H, J=7.5Hz), 3.21(m, 2H), 2.84 (m, 1H), 2.80 (m,1H), 2.72 (m, 1H), 2.58 (dd, 1H, J=13.5, 6.0 Hz), 1.83(m, 1H), 0.83(d,3H, J=6.3Hz), 0.77(d, 3H, J=6.6Hz),

Mass: ES-MS m/z 418 (M+H)⁺, 440 (M+Na)⁺

¹HNMR (300 MHz, DMSO−d₆) : δ11.95 (br, 1H), 10.31 (br, 1H), 7.74(d, 2H,J=8.7 Hz), 7.68 (d, 2H, J=8.7 Hz), 7.20 (m, 2H), 7.19 (m, 2H), 7.11 (m,1H), 5.49(d, 1H, J=5.1 Hz), 5.04(d, 1H, J=6.3 Hz), 4.83 (m, 1H),3.86(dd, 1H, J=9.0,6.0 Hz), 3.70(dd, 1H, J=9.0,6.0 Hz), 3.59 (m, 1H),3.58(m, 1H), 3.57 (m, 1H), 3.53 (m, 1H), 3.31 (m, 1H), 3.01 (m, 1H),3.00 (m, 1H), 2.75 (m, 2H), 2.72 (m, 1H), 244 (m, 1H), 2.06 (m, 1H),1.95 (m, 1H), 1.35 (m, 1H), 1.20 (m, 1H), 0.83 (d, 3H, J=6.6 Hz), 0.77(d, 3H, J=6.6 Hz)

Mass: ES-MS m/z 590 (M+H)⁺, 612 (M+Na)⁺

While the invention has been described with reference to above detaileddescription and the preferred examples, it is not intended to be limitedthereto. Therefore the above description should not be construed aslimiting, but merely as exemplifications of preferred embodiments. Forexample, the functions described above and implemented as the best modefor operating the present invention are for illustration purposes only.Other arrangements and methods may be implemented by those skilled inthe art without departing from the scope and spirit of this invention.Moreover, those skilled in the art will envision other modificationswithin the scope and spirit of the specification appended hereto.

1: A process for preparation of darunavir of Formula I or solvates or apharmaceutically acceptable salt thereof,

comprising: a) reacting4-amino-N-(2R,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamideof Formula II

with a (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivative in amixture of water immiscible organic solvent and water; and b) isolatingthe darunavir. 2: The process of claim 1, wherein the(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivative is(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol succinimidyl carbonate. 3:The process of claim 1, wherein the water immiscible organic solvent isselected from the group consisting of esters, ethers, halogenatedhydrocarbons, aromatic hydrocarbons and mixtures thereof. 4: The processof claim 3, wherein the water immiscible organic solvent is selectedfrom the group consisting of ethyl acetate, methyl tertiary butyl ether,methylene chloride, toluene and mixtures thereof. 5: (canceled) 6:(canceled) 7: (canceled) 8: The process of claim 1, wherein step b)comprises i) crystallizing darunavir from a carboxylic acid solvent; ii)isolating the corresponding darunavir carboxylic acid solvate; and iii)converting the darunavir carboxylic acid solvate in to darunavir. 9:(canceled) 10: (canceled) 11: The process of claim 8, wherein thecarboxylic acid solvent is propionic acid. 12: The process of claim 8,wherein the darunavir carboxylic acid solvate is darunavir propionatesolvate. 13: Darunavir propionate solvate. 14: Darunavir propionatesolvate, characterized by an X-Ray diffraction (XRD) patternsubstantially in accordance with FIG.
 1. 15: The process of claim 8,further comprising steps for making the4-amino-N-(2R,3S)(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamideof Formula II, which comprises 1) reacting a compound of Formula IV

wherein ‘P₁’ represents hydrogen or a suitable amine protecting group;with a protected benzene sulfonyl chloride of Formula IV′

wherein ‘P₂’ represents hydrogen or a suitable amine protecting group;to obtain a compound of Formula III

wherein ‘P₁’ and ‘P₂’ is defined as above; and 2) deprotecting theresultant compound with a suitable deprotecting medium to obtain acompound of Formula II

16: The process of claim 15, wherein the suitable amine protecting groupis selected from the group consisting of acetyl, tertiary butyloxycarbonyl (Boc), p-nitrobenzoyl (PNB), p-methoxybenzoyl (PMB), trityl andthe like. 17: The process of claim 15, wherein the “P₁” is tertiarybutyloxy carbonyl (Boc) group. 18: The process of claim 15, wherein the“P₂” is acetyl group. 19: The process of claim 15, wherein the step a)is carried out in an organic solvent in presence of a base. 20: Theprocess of claim 19, wherein the organic solvent is selected from thegroup consisting of halogenated hydrocarbons, aromatic hydrocarbons,ethers, amides, nitriles and the like and mixtures thereof. 21: Theprocess of claim 20, wherein the organic solvent is methylene chlorideor toluene. 22: The process of claim 19, wherein the base is selectedfrom the group consisting of sodium hydroxide, potassium hydroxide,lithium hydroxide, sodium carbonate, potassium carbonate, lithiumcarbonate, sodium bicarbonate, potassium bicarbonate, ammonia, methylamine, ethyl amine, dimethylamine, diethylamine, triethylamineN,N-diisopropyl ethyl amine, N,N-dimethylaniline, N,N-dimethylaminopyridine and the like and mixtures thereof. 23: (canceled) 24: Theprocess of claim 15, wherein the suitable deprotecting medium is an acidand an organic solvent. 25: The process of claim 24, wherein the acid isselected from the group consisting of hydrochloric acid, hydrobromicacid, sulfuric acid, perchloric acid, phosphoric acid, acetic acid,trifluoro acetic acid, trichloro acetic acid, methane sulfonic acid andthe like and mixtures thereof. 26: (canceled) 27: The process of claim24, wherein the organic solvent is selected from the group consisting oflower alcohols, nitriles, ethers, amides, water and mixtures thereof.28: (canceled) 29: (canceled) 30: (canceled) 31: (canceled) 32:(canceled) 33: (canceled) 34: (canceled) 35: (canceled) 36: The processof claim 15, wherein the darunavir carboxylic acid solvate obtained isconverted in to darunavir in amorphous form. 37: A process forpreparation of amorphous darunavir, comprising the steps of: a)providing a solution of darunavir or a solvate thereof in an acid and asolvent; b) combining the solution of step a) with a solution of a baseand water, c) recovering the amorphous darunavir. 38: The process ofclaim 37, wherein the step a) comprises dissolving darunavir or solvatesor a pharmaceutically acceptable salt thereof in an acid, a solvent anda base. 39: The process of claim 38, wherein the acid is selected fromthe group consisting of acetic acid, propionic acid, formic acid,trifluoroacetic acid, butanoic acid, pentanoic acid, hexanoic acid,heptanoic acid and the like and mixtures thereof. 40: (canceled) 41: Theprocess of claim 38, wherein the base is selected form the groupconsisting of ammonia, sodium carbonate, potassium carbonate, sodiumbicarbonate, potassium bicarbonate, cesium carbonate and the like andmixtures thereof. 42: (canceled) 43: The process of claim 38, whereinthe solvent is selected from the group consisting of nitriles, alcoholssuch as methanol, ethanol, isopropanol and the like; water and mixturesthereof. 44: (canceled) 45: The process of claim 37, wherein the base instep b) is selected from the group consisting of ammonia, sodiumcarbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, cesium carbonate and the like and mixtures thereof. 46:(canceled) 47: (canceled) 48: (canceled) 49: (canceled) 50: (canceled)51: (canceled) 52: (canceled) 53: (canceled)